The long-term goal of this project is to determine the function of the Wnt signaling pathway in the formation of the glial scar. After injury to the brain or spinal cord, a complex glial scar forms. In the acute phase of recovery, the glial scar promotes recovery by acting as a barrier to invading cells. In sub-acute and chronic phases, however, the scar inhibits the sprouting and regeneration of damaged axons and is therefore detrimental to full recovery. Wnts are soluble signaling molecules (morphogens) that regulate the proliferation, specification, and differentiation of neuronal and glial precursors. Following spinal cord injury (SCI), the expression of Wnts is up-regulated at the injury site. We propose that Wnt signaling promotes the proliferation of glial cells and delays or prevents the differentiation of precursor cells into myelinating oligodendrocytes. In the first aim, we will use a reporter mouse model to identify the glial cells in which Wnt signaling is activated after SCI. A combination of qRT-PCR and in situ hybridization will determine where and when different components of the Wnt signaling pathways are expressed. In the second aim, we will use conditional knock-out mouse models to eliminate Wnt signaling specifically in different types of glia after SCI and analyze the effects on glial cell proliferation and scar formation. We predict that the elimination of Wnt signaling will reduce proliferation and promote the remyelination of spared but damaged axons. In the third aim, we will evaluate the consequences of the elimination of Wnt signaling on functional recovery using an open-field test designed specifically for mice (Basso Mouse Scale, BMS). This project will lead to a fuller understanding of the factors that influence the formation of the glial scar after SCI and may lead to the development of new therapeutics capable of suppressing scar formation. PUBLIC HEALTH RELEVANCE: In this project we propose that Wnt plays a role promoting the proliferation of glial cells and delays or prevents the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes following spinal cord injury. Dissregulation of Wnt signaling is associated with various human cancers and much effort is being applied on developing therapeutics to regulate this pathway. The translational significance of this project is to evaluate the potential that these anti-tumor therapeutics may have on improving recovery following spinal cord injury